Abstract

Chronic exposure to the malaria parasite is required for full clinical protection, possibly due to improved survival versus maintenance of effector function of CD4 memory T cells (Tmem). IFN-γ is required for protection; therefore, we investigated the development of Th1 memory in chronic Plasmodium chabaudi malaria infection using ifng-reporter mice. We observed that the expression of Th1 markers (T-bet, CXCR3) peaked well before T cell contraction, suggesting poor long-term commitment to IFN- γ production. In addition, markers of T follicular helper cells (Tfh), such as CXCR5 and Bcl6, were on most Th1 cells, and some co-produced IL-21 and IL-10. While Th1 effector cells differentiate into CXCR3+ Tmem in malaria, they are Tbetlo and do not maintain ifng expression, unless they are dividing, though they do express Bcl6 and IL-21. Interestingly, Bcl6-deficient Th1 cells produce more IL-21, while infection of IL-10-deficient mice increased T cell expression of both T-bet and Bcl6, generating more mixed phenotype cells. P. chabaudi infected IL-10-/- mice die of T cell-mediated pathological inflammation, suggesting that the dominant Th1/Tfh phenotype is pathogenic if not regulated. Expression of Bcl6 and IL-21 in Th1 cells has been described as an early and transient event before full commitment; however, these results suggest that this intermediate stage can be maintained in chronic infection, potentially to prevent both exhaustion and pathology, via IL-10.